Method for treating diabetes employing an aP2 inhibitor and combination

Abstract

A method is provided for treating diabetes and related diseases, especially Type II diabetes, employing an aP2 inhibitor or a combination of an aP2 inhibitor and another antidiabetic agent such as metformin, glyburide, troglitazone and/or insulin.

1. A method for treating diabetes which comprises administering to a mammalian species in need of treatment a therapeutically effective amount of an aP2 inhibitor, wherein the aP2 inhibitor includes (a) an oxazole or analogous ring selected from the group consisting of a substituted benzoyl or biphenyl-2-oxazole-alkanoic acid derivative, an oxazole derivative, a 2-thio-4,5-diphenyloxazole S-derivative, a phenyl-heterocyclic oxazole derivative, a diaryloxazole derivative, a 4,5-diphenyloxazole derivative, an oxazole carboxylic acid derivative, a phenyloxazolyloxazole derivative, or a 2-(4,5-diaryl)-2-oxazolyl substituted phenoxyalkanoic acid derivative; and (b) a hydrogen bond donor or acceptor group and (c) an additional substituent which binds within and/or interacts with a discrete pocket within the aP2 protein defined by the amino acid residues designated Phe 16, Tyr 19, Met 20, Val 23, Val 25, Ala 33, Phe 57, Thr 74, Ala 75, Asp 76, Arg 78 in human aP2 (SEQ ID NO: 1). 
     
     
       2. The method as defined in  claim 1  wherein the aP2 inhibitor binds to the aP2 protein and inhibits its function and/or its ability to bind free fatty acids. 
     
     
       3. The method as defined in  claim 1  wherein said additional substituent in said aP2 inhibitor is hydrophobic in nature. 
     
     
       4. The method as defined in  claim 1  in which the through space distance from the hydrogen bond donor/acceptor group and the additional substituent group in said aP2 inhibitor is within the distance of about 7 to about 15 Angstroms. 
     
     
       5. The method as defined in  claim 1  wherein Type II diabetes is treated. 
     
     
       6. The method as defined in  claim 1  wherein the aP2 inhibitor is employed in the form of a pharmaceutically acceptable salt thereof or a prodrug ester thereof. 
     
     
       7. A method for treating diabetes which comprises administering to a mammalian species in need of treatment a therapeutically effective amount of an aP2 inhibitor, wherein the aP2 inhibitor is selected from the group consisting of:
 (I) a substituted benzoylbenzene or biphenyl alkanoic acid derivative having the structure of Formula I: A(CH 2 ) n O—B 
 
       wherein A is a group having the formula 
       
         
           
           
               
               
           
         
       
       wherein 
       X is —N—; Z is —S—, or —O—; 
       R 1  is hydrogen, lower alkyl or phenyl; 
       R 2  is hydrogen or lower alkyl; or 
       R 1  and R 2  taken together form a benzene ring; 
       n is 1-2; 
       B is 
       
         
           
           
               
               
           
         
       
       wherein 
       Y is OR 5  or N(OH)R 8 ; 
       R 4  and R 5  are each, independently, hydrogen or lower alkyl; 
       R 6  is hydrogen, halo or nitro; 
       R 7  is 
       
         
           
           
               
               
           
         
       
       R 8  is lower alkyl; 
       and 
       pharmacologically acceptable salts thereof;
 (II) oxazole derivatives which have the structure of Formula III 
 
       
         
           
           
               
               
           
         
       
       in which 
       R and R′ are identical or different and represent a hydrogen atom or an alkyl radical containing 1 or 2 carbon atoms, 
       R 1  and R 2  are identical or different and represent hydrogen or halogen atoms or alkyloxy radicals in which the alkyl portion contains 1 to 4 carbon atoms in a straight or branched chain, and n equals 3 to 6 and pharmaceutically acceptable salts thereof;
 (III) 2-thiol-4,5-diphenyloxazole S-derivatives which have the structure of Formula III: 
 
       
         
           
           
               
               
           
         
       
       wherein m is 0, 1 or 2, n is 1 and 
       R represents hydroxy, alkoxy or amino, and 
       pharmaceutically acceptable addition salts thereof;
 (IV) azole derivatives of the structure of Formula IV: 
 
       
         
           
           
               
               
           
         
       
       wherein 
       R 1  is carboxyl, esterified carboxyl or other functionally modified carboxyl group; 
       R 2  and R 3  each are aryl of up to 10 carbon atoms; 
       A is C n H 2n  in which n is an integer from 1 to 10, inclusive; 
       Z is O or S, and 
       physiologically acceptable salts thereof
 (V) phenyl-heterocyclic oxazole derivatives which have the structure of Formula V: 
 
       
         
           
           
               
               
           
         
       
       wherein X is 
       
         
           
           
               
               
           
         
       
       R is CH 2 R 2 ; 
       R 1  is Ph or Th; 
       R 2  is 
       
         
           
           
               
               
           
         
       
       CO 2 R 3  where R 3  is H, or C 1 -C 4  lower alkyl; and pharmaceutically acceptable salt thereof;
 (VI) diaryloxazole derivatives having the structure of Formula VI: 
 
       
         
           
           
               
               
           
         
       
       wherein R 1  is carboxy or protected carboxy, 
       R 2  is aryl, 
       R 3  is aryl, 
       A 1  is lower alkylene, 
       A 2  is bond or lower alkylene and 
       —Q— is 
       
         
           
           
               
               
           
         
       
       in which 
       
         
           
           
               
               
           
         
       
       is cyclo (lower)alkane or cycle(lower)alkene, each of which may have substituent(s);
 (VII) 4,5-diphenyloxazole derivatives having the structure of Formula VIIA: 
 
       
         
           
           
               
               
           
         
       
       wherein 
       R is H or C 1 -C 5  lower alkyl, 
       X is N or CH, 
       Y is H or CO 2 R 1 , or COR 2 , provided that when X is CH, Y is not H, 
       R 1  is C 1 -C 5  lower alkyl, or phenylmethyl, and
 R 2  is C 1 -C 5  alkyl; or of Formula VIIB: 
 
       
         
           
           
               
               
           
         
       
       wherein 
       R is H or C 1 -C 5  lower alkyl, 
       X is (CH 2 ) n  or para or meta substituted phenyl wherein the substituent is OR 2 , 
       R 2  is C 1 -C 5  alkyl, and 
       n is an integer of 4 to 8, and 
       pharmaceutically acceptable salts thereof
 (VIII) oxazole carboxylic acid derivatives having the structure of Formula VIII: 
 
       
         
           
           
               
               
           
         
       
       wherein 
       Y and Z are independently hydrogen or together form a bond; 
       X is CN, CO 2 R 1  or CONR 2 R 3 ; 
       R and R 1  are independently or together H, Na, or C 1 -C 5  lower alkyl; 
       R 2  and R 3  are independently or together H, or C 1 -C 5  lower alkyl; and alkali metal salts thereof;
 (IX) phenyloxazolyloxazole derivatives having the structure of Formula IX: 
 
       
         
           
           
               
               
           
         
         wherein X is 
       
       
         
           
           
               
               
           
         
       
       Y is CH 3 , Ph, or OH, provided that when Y is OH, the compound exists in the keto-enol tautaumerism form 
       
         
           
           
               
               
           
         
       
       R 1  is Ph or Th; 
       R 2  is CH 2 R 3 ; 
       R 3  is CO 2 R 4 ; 
       R 4  is H or C 1 -C 5  lower alkyl; 
       R 5  is H or CH 3 ; 
       R 6  is OHCHN or H 2 N; and 
       R 7  is H or OH; and 
       pharmaceutically acceptable salt thereof;
 (X) 2-(4,5-diaryl)-2-oxazolyl substituted phenoxyalkanoic acids and esters having the structure of Formula XA: 
 
       
         
           
           
               
               
           
         
       
       of Formula XB: 
       
         
           
           
               
               
           
         
       
       wherein n is 7-9 and R is hydrogen or lower alkyl; or 
       wherein R is hydrogen, or the alkali metal salt thereof, of Formula XC: 
       
         
           
           
               
               
           
         
       
       of Formula XD: 
       
         
           
           
               
               
           
         
       
       wherein 
       R 1  is phenyl or thienyl; 
       R 2  is hydrogen, lower alkyl or together with CO 2  is tetrazol-1-yl; 
       X is a divalent connecting group selected from the group consisting of CH 2 CH 2 , CH═CH, and CH 2 O; 
       Y is a divalent connecting group attached to the 3- or 4-phenyl position selected from the group consisting of OCH 2 , CH 2 CH 2  and CH═CH, or when R 2  is hydrogen, an alkali metal salt thereof;
 (XI) substituted 4,5-diaryl heterocycles having the structure of Formula XI: 
 
       
         
           
           
               
               
           
         
       
       wherein 
       each group Ar is the same or different and is optionally substituted phenyl or optionally substituted heteroaryl; 
       X is nitrogen; 
       Y is C(CH 2 ) n A; 
       Z is oxygen, and the dotted line indicates the optional presence of a double bond so as to form a fully unsaturated heterocyclic ring; 
       n is 4 to 12; and 
       A is CO 2 H or a group hydrolysable to CO 2 H, 5-tetrazolyl, SO 3 H, P(O)(OR) 2 , P(O)(OH) 2 , or 
       P(O)(R)(OR) in which R is hydrogen or C 1−4 alkyl; and 
       pharmaceutically acceptable salts thereof;
 (XII) compounds which have the structure of Formula XII: 
 
       
         
           
           
               
               
           
         
       
       wherein X is O or S; 
       R 1  is H, phenyl or phenyl substituted with F, Cl or Br or alkoxy, 
       R 2  is H, alkyl, phenyl or phenyl substituted with F, Cl or Br or alkoxy, and 
       R 3  is H or alkyl. 
     
     
       8. The method as defined in  claim 1  wherein the aP2 inhibitor has the structure